Mechanisms and translation of lipid resuscitation

脂质复苏的机制和转化

• 批准号: 8333735
• 负责人: Israel Rubinstein
• 金额: --
• 依托单位: JESSE BROWN VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-10-01 至 2016-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8333735
• 关键词: Accounting; Acute; Admission activity; Adrenergic beta-Antagonists; Aging; Alcohols; American; American Heart Association; Animal Model; Animals; Antidotes; Award; Binding; Blood capillaries; Blood flow; Brain; Bupivacaine; Bypass; Calcium Channel Blockers; Cardiac; Cardiopulmonary Resuscitation; Cardiotoxicity; Cardiovascular Physiology; Case Study; Cells; Cessation of life; Cocaine; Conduction Anesthesia; Cyclodextrins; Data Set; Development; Diffusion; Drug Prescriptions; Drug abuse; Drug toxicity; Elderly; Electron Microscopy; Emulsions; Endothelium; Fatty acid glycerol esters; Funding; Generic Drugs; Goals; Great Britain; Guidelines; Gunshot wound; Health; Heart; Histologic; Indium; Information Systems; Infusion procedures; Inpatients; Instruction; Intoxication; Intravenous Fat Emulsions; Ireland; Ischemia; Life; Lipids; Liposomes; Local Anesthetics; Measures; Medical; Metabolic; Military Personnel; Modification; Morbidity - disease rate; Myocardial; Neurologic; Neurologic Manifestations; Normal tissue morphology; Organ; Outcome; Overdose; Pharmaceutical Preparations; Phase; Physicians; Plasma; Play; Poisoning; Population; Prevalence; Process; Publishing; Radiolabeled; Rattus; Reaction Time; Recovery; Reperfusion Therapy; Resistance; Resuscitation; Risk; Signal Transduction; Site; Societies; Symptoms; Testing; Time; Tissues; Toxic effect; Toxicity Tests; Toxin; Translating; Translations; Treatment Protocols; Tricyclic Antidepressive Agents; United States; Veterans; Work; aqueous; base; capillary; clinical practice; cocaethylene; cocaine overdose; cocaine use; effective therapy; fatty acid metabolism; improved; in vivo; inhibitor/antagonist; light microscopy; migration; nanomedicine; novel; novel strategies; particle; patient safety; prevent; radiotracer; research study; soy; uptake; vehicular accident

DESCRIPTION (provided by applicant): Work funded under the PI's previous VA Merit award has contributed directly to a novel and now widely accepted life-saving treatment for local anesthetic systemic toxicity (LAST). Intravenous lipid emulsion (ILE) resuscitation has also been used in many instances to rapidly reverse acute cardiac and neurological symptoms of toxicity caused by a wide range of lipophilic (fat soluble) medications. In many published case reports involving LAST or other overdoses, ILE was effective even after standard resuscitation measures had failed. ILE is now a principle element in treatment guidelines published by the American Society of Regional Anesthesia, the Anaesthetists of Great Britain and Ireland, the Resuscitation Council (UK) and was added to the most recent American Heart Association ACLS guidelines for treating LAST. Drug overdose is the second leading cause of accidental death in the United States contributing to 36,000 fatalities in 2007 placing it ahead of gunshot wounds and just behind motor vehicle accidents. Moreover, veterans are at particular risk given the prevalence of both illicit drug abuse and the difficulty for a geriatric population to adhere to instructions for such prescription drugs as long acting calcium channel blockers that can be potentially fatal in overdose. Notably, ILE has been used effectively in treating overdose of many common prescription medications (e.g. beta blockers, tricyclic antidepressants or calcium channel blockers) that can be highly resistant to standard resuscitation measures. Identifying the precise mechanism(s) underlying ILE holds the promise of improving its efficacy and providing an effective, generic antidotal treatment for a range of life-threatening toxic drug overdoses. However, the precise mechanisms of ILE are not well understood. The conventional explanation involves partitioning of the offending toxin into the newly created lipemic plasma phase, or 'lipid sink'. However, even this mechanism has not been tested rigorously in vivo. Moreover, we have observed that key aspects of ILE cannot be explained by the sink alone, indicating that other, less well-understood, mechanisms are also at play. We believe that ILE also directly benefits cardiovascular function and have confirmed in preliminary experiments that the infusion of lipid emulsion in the intact rat exerts positive effecs on cardiac contractility and aortic blood flow. We hypothesize that this results in part from direc, positive effects of fatty acid metabolism on cardiac function. Moreover, it is well-established tha tissue ischemia can cause intercellular endothelial gaps to expand, thereby allowing liposomes to migrate into the myocardial interstitium. Such passive targeting of lipid particles, essentially nano-medicine, will bypass the normal tissue barriers to diffusion of drug away from cells and diminish the response time to lipid signal effectors. We hypothesize that extravascular migration of lipid particles contributes to the overall efficacy of ILE in reversing cardiac drug toxicity. W propose studies to test the metabolic effects of ILE and transendothelial migration of lipid particles. Finally, we seek to improve the translation of ILE to cocaine-related toxicity and longer-lasting overdoses such as calcium channel blocker toxicity. Improved patient safety and outcomes from drug toxicity are the over-arching goals of this project.

描述（由申请人提供）： PI之前的VA Merit奖资助的工作直接促成了一种新颖的，现在被广泛接受的局部麻醉全身毒性（LAST）的救生治疗。静脉注射脂肪乳剂（ILE）复苏也已在许多情况下用于快速逆转由各种亲脂性（脂溶性）药物引起的急性心脏和神经毒性症状。在许多已发表的涉及LAST或其他药物过量的病例报告中，即使在标准复苏措施失败后，ILE仍有效。ILE现在是由美国区域麻醉学会、英国和爱尔兰麻醉师协会、复苏理事会（英国）发布的治疗指南中的一个原则要素，并被添加到最新的美国心脏协会ACLS治疗LAST指南中。药物过量是美国意外死亡的第二大原因，2007年造成36，000人死亡，排在枪伤之前，仅次于机动车事故。此外，退伍军人面临的风险特别大，因为非法药物滥用普遍，老年人很难遵守长效钙通道阻滞剂等处方药的说明，这些药物过量可能致命。值得注意的是，ILE已有效用于治疗许多常见处方药（例如β受体阻滞剂，三环抗抑郁药或钙通道阻滞剂）的过量，这些药物对标准复苏措施具有高度抵抗性。确定ILE的确切机制有望提高其疗效，并为一系列危及生命的毒性药物过量提供有效的通用解毒治疗。然而，ILE的确切机制还不清楚。传统的解释涉及到入侵毒素进入新创建的脂血血浆相，或“脂质库”的分区。然而，即使是这种机制也没有在体内进行严格的测试。此外，我们已经观察到，ILE的关键方面不能单独用水槽来解释，这表明其他不太清楚的机制也在发挥作用。我们认为，ILE也直接有益于心血管功能，并在初步实验中证实，在完整大鼠中输注脂肪乳剂对心肌收缩力和主动脉血流量产生积极影响。我们推测这部分是由于脂肪酸代谢对心脏功能的直接、积极作用。此外，已经确定的是，组织缺血可以引起细胞间内皮间隙扩大，从而允许脂质体迁移到心肌细胞中。这种脂质颗粒的被动靶向，基本上 纳米药物将绕过正常组织的屏障，使药物从细胞中扩散出去，并缩短对脂质信号效应物的反应时间。我们假设脂质颗粒的血管外迁移有助于ILE逆转心脏药物毒性的总体疗效。我们建议进行研究，以测试代谢的影响，ILE和跨内皮迁移的脂质颗粒。最后，我们寻求改善ILE向可卡因相关毒性和更长持续过量（如钙通道阻滞剂毒性）的转化。改善患者的安全性和药物毒性的结果是该项目的首要目标。